Substituted cyclohexanols as central nervous system agents

ABSTRACT

Substituted cyclohexanols and cyclohexylamines and derivatives thereof are described, as well as methods for the preparation and pharmaceutical composition of same, which are useful as central nervous system agents and are particularly useful as dopaminergic, antipsychotic, and antihypertensive agents as well as for treating hyperprolactinaemia-related conditions and central nervous system disorders.

This is a continuation-in-part of U.S. application Ser. No. 446,901,filed Dec. 6, 1989, which application issued Sept. 18, 1990, as U.S.Pat. No. 4,957,921.

BACKGROUND OF THE INVENTION

The present invention relates to novel substituted cyclohexanols andcyclohexylamines and derivatives thereof useful as pharmaceuticalagents, to methods for their production, to pharmaceutical compositionswhich include these compounds and a pharmaceutically acceptable carrier,and to pharmaceutical methods of treatment. The novel compounds of thepresent invention are central nervous system agents. More particularly,the novel compounds of the present invention are dopaminergic agents.

A series of 1-(4-arylcyclohexyl)piperidines which may structurally berepresented by the formula ##STR1## the pharmaceutically acceptable acidaddition salts and the stereochemically isomeric forms thereof, wherein

Ar¹ is a member selected from the group consisting of aryl and1,3-benzodioxolyl;

R is a member selected from the group consisting of hydrogen and loweralkyl;

R¹ is a member selected from the group consisting of hydrogen, cyano,carboxyl, lower alkyloxycarbonyl, aryllower alkyloxycarbonyl,aminocarbonyl, mono- and di(lower alkyl)aminocarbonyl, mono- anddi(aryllower alkyl)aminocarbonyl, (aryllower alkyl)lower alkylaminocarbonyl, hydroxy, lower alkyloxy, lower alkylcarbonyloxy, formyl, loweralkylcarbonyl, arylcarbonyl, aryllower alkylcarbonyl, lower alkyl, loweralkenyl, lower alkynyl and cyclohexyl; and

A is a bivalent radical, having the formula ##STR2## wherein R² and R³are each independently selected from the group consisting of hydrogen,halo, trifluoromethyl, lower alkyl, and lower alkyloxy; or

A is a bivalent radical, having the formula ##STR3## wherein Ar² isaryl, and

R⁴ is a member selected from the group consisting of hydrogen, loweralkyl, aryllower alkyl, cyanolower alkyl, aminolower alkyl, mono- anddi(lower alkyl) aminolower alkyl, mono- and di(arylloweralkyl)aminolower alkyl, [(aryllower alkyl)lower alkylamino]lower alkyl,hydroxylower alkyl, mercaptolower alkyl, lower alkyloxylower alkyl,lower alkylthiolower alkyl, aryloxylower alkyl, arylthiolower alkyl,aryllower alkyloxylower alkyl, aryllower alkylthiolower alkyl, and aradical of formula ##STR4## wherein n is 0 or an integer of from 1 to 6inclusive, Q is O, S or NR⁶, p is 0 or 1, X is O or S, R⁵ is hydrogen,lower alkyl, aryl or aryllower alkyl, m is 0 or 1 and Y is O, S or NR⁶,wherein R⁶ as used in the definition of Q and Y is hydrogen, loweralkyl, aryl or aryllower alkyl;

provided that when Y is O and m and p are each 1, then R⁵ is other thanhydrogen and provided that when p is 1 then n is other than 0;

wherein aryl is a member selected from the group consisting of phenyl,thienyl, pyridinyl, naphthalenyl and substituted phenyl, saidsubstituted phenyl having from 1 to 3 substituents each independentlyselected from the group consisting of halo, lower alkyl, lower alkyloxy,phenyl lower alkyloxy, trifluoromethyl, nitro, amino and hydroxy aredisclosed in U.S. Pat. No. 4,329,353 as having psychotropic andantiemetic activity.

A series of 4-alkoxy-4-(substituted phenyl)cyclohexylamines of formula##STR5## where the sign indicates the cis or trans configuration withthe condition that when the R₃ O bond is cis with respect to the aminogroup the bond joining the phenyl and cyclohexyl rings is trans and viceversa; R=1-4C alkyl, Cl, F, Br, CFs, or 1-4C alkoxy; R'=R or H; R₁ =H or1-4C alkyl; R₂ =H, 1-4C alkyl, aroylalkyl (monosubstituted on the arylring by a group R or 6-10C aryl) or bis-arylalkyl (monosubstituted onthe ring by a group R' or 6-10C aryl) or R₁ and R₂ together with the Natom form a saturated heterocyclic chosen from pyrrolidino, piperidino,hexamethyleneimino, morpholino, and piperazino (optionallymonosubstituted); R₃ =1-4C. alkyl; are disclosed in Belgium Patent790836 as having central nervous system depressant activity.

However, the 1-(4-arylcyclohexyl)piperidines disclosed in U.S. Pat. No.4,329,353 and the 4-alkoxy-4-(substituted phenyl)-cyclohexylaminesdisclosed in Belgium Patent 790836 do not disclose or suggest thecombination of structural variations of the compounds of the presentinvention described hereinafter.

SUMMARY OF THE INVENTION

Accordingly, the present invention is a compound of Formula I ##STR6##wherein R is --OR³, wherein R³ is hydrogen, lower alkyl, cycloalkyl,cycloalkylalkyl, aryl lower alkyl, lower alkanoyl, aroyl, or aryl loweralkanoyl, ##STR7## wherein R⁴ and R⁵ are each independently hydrogen,lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aryl loweralkyl, heteroaryl lower alkyl, lower alkanoyl, cycloalkanoyl,cycloalkylalkanoyl, aryl lower alkanoyl, heteroaryl lower alkanoyl,aroyl, heteroaroyl, or R⁴ and R⁵ are taken together with the nitrogenatom to which they are attached to form a ring denoted by ##STR8##wherein p is zero or an integer from 1 to 4 and R⁶ is hydrogen, loweralkyl, cycloalkyl, or cycloalkylalkyl ##STR9## wherein X is oxygen orsulfur or ##STR10## wherein R⁶ is as defined above, or ##STR11## whereinR⁴ and R⁵ are each independently hydrogen, lower alkyl, cycloalkyl,cycloalkylaklkyl, aryl, aryl lower alkyl, lower alkanoyl, aryl loweralknaoyl, aroyl, or R⁴ and R⁵ are taken together with the oxygen andnitrogen atoms to which they are attached to form a ring denoted by##STR12## wherein q is an integer from 2 to 3 and R⁶ is as definedabove;

m is zero or an integer from 1 to 2;

R¹ is hydrogen, aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinylsubstituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl,lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted bylower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2-or3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolylor 2-, 4-, or 5-thiazolyl substituted by lower alkyl or halogen; n iszero or an integer from 1 to 4; R² is ##STR13## wherein R⁷ is aryl, 2-,3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl substituted by lower alkyl,lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl or 2-, 4-, or5-pyrimidinyl substituted by lower alkyl, lower alkoxy, or halogen,2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, lower alkoxy, orhalogen, 2- or 3-thienyl or 2- or 3-thienyl substituted by lower alkylor halogen, 2- or 3-furanyl or 2- or 3-furanyl substituted by loweralkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, or 5-thiazolylsubstituted by lower alkyl or halogen; and the corresponding cis andtrans isomers thereof; or a pharmaceutically acceptable acid additionsalt thereof.

As dopaminergic agents, the compounds of Formula I are useful asantipsychotic agents for treating psychoses such as schizophrenia. Theyare also useful as antihypertensives and for the treatment of disorderswhich respond to dopaminergic activation. Thus, other embodiments of thepresent invention include the treatment, by a compound of Formula I, ofhyperprolactinaemia-related conditions, such as galactorrhea,amenorrhea, menstrual disorders and sexual dysfunction, and severalcentral nervous system disorders such as Parkinson's disease,Huntington's chorea, and depression. In addition, like many knownantipsychotics, these compounds are high affinity ligands for thecentral nervous system sigma binding site.

A still further embodiment of the present invention is a pharmaceuticalcomposition for administering an effective amount of a compound ofFormula I in unit dosage form in the treatment methods mentioned above.

Finally, the present invention is directed to methods for production ofa compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of Formula I, the term "lower alkyl" means a straightor branched hydrocarbon radical having from one to six carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.

The term "cycloalkyl" means a three- to seven-member saturatedhydrocarbon ring and includes, for example cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term "cycloalkylalkyl' means a cycloalkyl group as defined aboveattached to a lower alkyl group as defined above and includes, forexample, cyclopropylmethyl, cyclohexylmethyl, and the like.

The term "aryl" means an aromatic radical which is a phenyl group orphenyl group substituted by one to four substituents selected from loweralkyl, lower alkoxy, lower thioalkoxy, halogen or trifluoromethyl suchas, for example, benzyl, phenethyl, and the like.

The term "heteroaryl" means a heteroaromatic radical which is 2-, 3-, or4-pyridinyl or 2-, 3-, or 4-pyridinyl substituted by lower alkyl, loweralkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinylsubstituted by lower alkyl, lower alkoxy, or halogen, 2-pyrazinyl or2-pyrazinyl substituted by lower alkyl, lower alkoxy, or halogen, 2- or3-thienyl or 2- or 3-thienyl substituted by lower alkyl or halogen, 2-or 3-furanyl or 2-or 3-furanyl substituted by lower alkyl or halogen,2-, 4-, or 5-thiazolyl or 2- 4-, or 5-thiazolyl substituted by loweralkyl or halogen.

The term "aryl lower alkyl" means an aromatic radical, as defined above,attached to a lower alkyl group as defined above.

The term "heteroaryl lower alkyl" means a heteroaromatic radical, asdefined above, attached to a lower alkyl group as defined above.

The term "lower alkanoyl" means a lower alkyl group as defined aboveattached to a carbonyl group which is then attached to the parentmolecular residue.

The term "cycloalkanoyl" means a cycloalkyl ring as defined aboveattached to a carbonyl group which is then attached to the parentmolecular residue and includes for example, cyclopropanoyl,cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, cycloheptanoyl, and thelike.

The term "cycloalkylalkanoyl" means a cycloalkyl ring as defined aboveattached to a lower alkanoyl group as defined above.

The term "aryl lower alkanoyl" means an aromatic radical, as definedabove, attached to a lower alkanoyl group as defined above.

The term "heteroaryl lower alkanoyl" means a heteroaromatic radical, asdefined above, attached to a lower alkanoyl group as defined above.

The term "aroyl" means an aromatic radical as defined above attached toa carbonyl group which is then attached to the parent molecular residue.

The term "heteroaroyl" means a heteroaromatic radical as defined aboveattached to a carbonyl group which is then attached to the parentmolecular residue.

"Lower alkoxy" and "thioalkoxy" are O-alkyl or S-alkyl of from one tosix carbon atoms as defined above for "lower alkyl."

"Halogen" is fluorine, chlorine, bromine, or iodine.

"Alkali metal" is a metal in Group IA of the periodic table andincludes, for example, lithium, sodium, potassium, and the like.

"Alkaline-earth metal" is a metal in Group IIA of the periodic table andincludes, for example, calcium, barium, strontium, magnesium and thelike.

"Noble metal" is platinum, palladium, rhodium, ruthenium, and the like.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids, such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,phosphorous, and the like, as well as the salts derived from nontoxicorganic acids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Suchsalts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated aresalts of amino acids such as arginate and the like and gluconate,galacturonate (see, for example, Berge, S. M., et al, "PharmaceuticalSalts," Journal of Pharmaceutical Science, Vol. 66, pages 1-19 (1977)).

The acid addition salts of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the presentinvention.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

The compounds of the present invention may exist as a mixture of cis andtrans isomers or as the individual cis and trans isomers. The mixture ofisomers as well as the individual isomers are intended to be encompassedwithin the scope of the present invention.

A preferred compound of Formula I is one wherein

R is --OR³, wherein R³ is hydrogen or lower alkanoyl, ##STR14## whereinR⁴ is hydrogen, cycloalkyl, cycloalkylalkyl, lower alkanoyl, aroyl, aryllower alkanoyl, or heteroaroyl and r⁵ is hydrogen or lower alkyl or;##STR15## wherein one of R⁴ or R⁵ is hydrogen and the other is hydrogen,lower alkyl, cycloalkyl, cycloalkyalkyl, aryl, or lower alkanoyl;

m is zero;

R¹ is hydrogen, phenyl, phenyl substituted by para lower alkyl, paralower alkoxy, para lower thioalkoxy, or para halogen, 2-, 3-, or4-pyridinyl, 2-, or 3-furanyl, 2- or 3-thienyl, 2-, 4-, or 5-thiazolyl,or 2-, 4-, or 5-pyrimidinyl;

n is zero or an integer from 1 to 3; and

R² is ##STR16## wherein R⁷ is phenyl, phenyl substituted by para loweralkyl, para lower alkoxy, para lower thioalkoxy, or para halogen, 2-,3-, or 4-pyridinyl, 2- or 3-furanyl, 2- or 3-thienyl, 2-, 4-, or5-thiazolyl, or 2-, 4-, or 5-pyrimidinyl.

Another preferred embodiment is a compound of Formula I wherein

R is --OH, ##STR17## wherein R⁴ is hydrogen, cycloalkyl,cycloalkylalkyl, lower alkanoyl, aroyl or heteroaroyl and R⁵ is hydrogenor lower alkyl; or

--NHOR⁴, wherein R⁴ is hydrogen, lower alkyl, cycloalkyl,cycloalkylalkyl, aryl, or lower alkanoyl;

m is zero;

R¹ is hydrogen, phenyl, phenyl substituted by para lower alkyl or parahalogen, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 2-, 4-, or5-thiazolyl, or 2-, 4-, or 5-pyrimidinyl;

n is zero or an integer from 1 to 2; and

R² is ##STR18## wherein R⁷ is hydrogen, phenyl, phenyl substituted bypara lower alkyl or para halogen, 2-, 3-, or 4-pyridinyl, 2- or3-thienyl, 2-, 4-, or 5-thiazolyl, or 2-, 4-, or 5-pyrimidinyl.

Particularly valuable are:

[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thienyl)cyclohexanol(mixture of cis/trans);

cis-4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thienyl)cyclohexanol;

trans-4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thienyl)cyclohexanol;

1-Phenyl-4-[2-4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol (mixtureof cis/trans);

1-(2-Pyridinyl)-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethylcyclohexanol(mixture of cis/trans);

1-(4-Fluorophenyl)-4-[2-4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol(mixture of cis/trans);

cis-1-(4-Methoxyphenyl)-4-2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol;

trans-1-(4-Methoxyphenyl)-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol;

4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thiazolyl)cyclohexanol(mixture of cis/trans);

1-(3-Pyridinyl)-4-[2-[4-(2-pyridinyl)-1-piperazinylethyl]cyclohexanol(mixture of cis/trans);

cis-1-(2-Pyridinyl)-4-[2-[3,6-dihydro-4-phenyl-1(2H)-pyridinyl]ethyl]cyclohexanol;

cis-1-(3-Pyridinyl)-4-[2-[3,6-dihydro-4-phenyl-1(2H)-pyridinyl]ethyl]cyclohexanol;

cis-4-[2-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)ethyl]-1-(2-thienyl)cyclohexanol;

4-2-4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(3-thienyl)cyclohexanol(mixture of cis/trans);

trans-4-[[4-(2-Pyridinyl)-1-piperazinyl]methyl]-1-(2-thienyl)cyclohexanol;

cis-4-[[4-(2-Pyridinyl)-1-piperazinyl]methyl]-1-(2-thienyl)cyclohexanol;

trans-1-(2-Pyridinyl)-4-[4-(2-pyrimidinyl)-1-piperazinyl]cyclohexanol;

cis-1-(2-Pyridinyl)-4-[4-(2-pyrimidinyl)-1-piperazinyl]cyclohexanol;

trans-1-(2-Pyridinyl)-4-[4-(2-pyridinyl)-1piperazinyl]cyclohexanol;

cis-1-(2-Pyridinyl)-4-4-(2-pyridinyl)-1-piperazinyl]cyclohexanol;

trans-1-(3-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol;

cis-1-(3-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol

4-[4-(2-Pyridinyl)-1-piperazinyl]-1-(2-thienyl)cyclohexanol (mixture ofcis/trans);

4-[4-(2-Pyridinyl)-1-piperazinyl-1-(3-thienyl)cyclohexanol (mixture ofcis/trans);

trans-1-(4-Chlorophenyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol;

cis-1-(4-Chlorophenyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol;

1-(4-Methoxyphenyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol(mixture of cis/trans);

1-Phenyl-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol (mixture ofcis/trans);

4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(2-pyridinyl)cyclohexanol(mixture of cis/trans);

trans-4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(3-pyridinyl)cyclohexanol;

cis-4-[3,6-Dihydro-4-phenyl-1(2H)-pyridinyl]-1(3-piperazinyl)cyclohexanol;

trans N-[4-[4-(2-Pyridinyl)-1-piperazinyl]cyclohexyl]benzamide;

transN-[4-[4-(2-Pyridinyl)-1-piperazinyl]cyclohexyl]-2-methoxybenzamide;

trans N-Methyl-N-[4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexyl]benzamide;

trans 4-Chloro-N-[4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexyl]benzamide;

transN-[4-[4-(2-Pyridinyl)-1-piperazinyl]cyclohexyl]-2-thiophenecarboxamide;

transN-[4-[4-(2-Pyridinyl)-1-piperazinyl]cyclohexyl]-3-thiophenecarboxamide;

trans N-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]benzamide;

transN-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]-2-thiophenecarboxamide;

transN-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]-3-thiophenecarboxamide;

transN-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]-3-pyridinecarboxamide;

transN-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]cyclohexanecarboxamide;

trans 4-Methyl-N-[4-[4-(2-pyridinyl)-1-piperazinylcyclohexyl]benzamide;

trans N-4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;

cis N-[4-2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;

trans4-Methyl-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;

cis4-Methyl-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;

cis4-Chloro-N-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;

trans4-Chloro-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethylcyclohexyl]benzamide;

trans N-[4-2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]acetamide;

trans3,4-Dichloro-N-[4-2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;

trans N-[4-[[4-(2-Pyridinyl)-1-piperazinyl]methyl]cyclohexyl]benzamide;

cis3,4-Dichloro-N-[4-[2-[4-(2-pyridinyl)-1piperazinyl]ethyl]cyclohexyl]benzamide;

trans 4-Chloro-N-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]benzamide;

transN-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]-4-fluorobenzamide;

transN-[4[4-(2-Pyridinyl)-1-piperazinyl]methyl]cyclohexyl]-3-thiophenecarboxamide;

trans4-Methoxy-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;

cis-N-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]-3-thiophenecarboxamide;

cisN-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]-2-furancarboxamide;

cis4-Methoxy-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;

cisN-[4-[2-(3,6-Dihydro-4-phenyl-1(2H)pyridinyl)ethyl]cyclohexyl]benzamide;

cisN-[4-[2-(3,6-Dihydro-4-phenyl-1(2H)pyridinyl)ethyl]cyclohexyl]-2-thiophenecarboxamide;

transN-[4-[2-(3,6-Dihydro-4-phenyl-1(2H)pyridinyl)ethyl]cyclohexyl]-2-thiophenecarboxamide;

transN-[4-[2-(3,6-Dihydro-4-phenyl-1(2H)pyridinyl)ethyl]cyclohexyl]benzamide;

transN-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]-2-thiophenecarboxamide;and

cisN-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]-2-thiophenecarboxamide;or a pharmaceutically acceptable acid addition salt thereof.

The compounds of Formula I are valuable dopaminergic agents. The testsemployed indicate that compounds of Formula I possess dopaminergicactivity. Thus, the compounds of Formula I were tested for their abilityto inhibit locomotor activity in mice according to the assay describedby J. R. McLean, et al, Pharmacology, Biochemistry and Behavior, Volume8, pages 97-99 (1978); for their ability to inhibit [³ ]-spiroperidolbinding in a receptor assay described by D. Grigoriadis and P. Seeman,Journal of Neurochemistry, Volume 44, pages 1925-1935 (1985); and fortheir ability to inhibit dopamine synthesis in rats according to theprotocol described by J. R. Walters and R. H. Roth,Naunyn-Schmiedeberg's Archives of Pharmacology, Volume 296, pages 5-14(1976). The above test methods are incorporated herein by reference. Thedata in the table show the dopaminergic activity of representativecompounds of Formula I. Additionally, the compounds of Formula I areligands for the sigma opiate binding site. The data in the table showthe inhibition of [³ H] DTG (ditoluoyl guanidine; a sigma ligand)binding by representative compounds of Formula I, according to themethod of E. Weber, et al, Proceedings of the National Academy ofSciences, USA, Volume 83, pages 8784-8788 (1986).

    __________________________________________________________________________    Biological Activity of Compounds of Formula I                                                                    Inhibition                                                                              Effects on                                                 Inhibition of                                                                          of Locomotor                                                                            Brain Striatal                                                                          Inhibition                                       [.sup.3 H]-Spiroperidol                                                                Activity  Dopamine Synthesis                                                                      of [.sup.3 H] DTG      Example                   Binding  in Mice   in Rats at                                                                              Binding                Number                                                                              Compound            IC.sub.50 nM                                                                           ED.sub.50 , mg/kg, IP                                                                   10 mg/kg, IP                                                                            IC.sub.50              __________________________________________________________________________                                                           nM                      1    trans-1-(4-Chlorophenyl)-4-[4-(2-                                                                 333      2.3                                              pyridinyl)-1-piperazinyl]cyclohexanol                                    1a   cis-1-(4-Chlorophenyl)-4-[4-(2-                                                                   816      0.86                                             pyridinyl)-1-piperazinyl]cyclohexanol                                    3    cis-4-[2-[4-(2-Pyridinyl)-1-piperazinyl]-                                                         262      1.3       67% inhibition                                                                          6.0                          ethyl]-1-(2-thienyl)cyclohexanol                                         4    trans-4-[2-[4-(2-Pyridinyl)-1-piperazinyl]-                                                       341      1.1       47% inhibition                                                                          5.0                          ethyl]-1-(2-thienyl)cyclohexanol                                         5    1-Phenyl-4-[2-[4-(2-pyridinyl)-1-                                                                 537      1.8       35% inhibition                         piperazinyl]ethyl]cyclohexanol (mixture                                       of cis/trans)                                                            6    1-(2-Pyridinyl)-4-[2-[4-(2-pyridinyl)-                                                            1047     0.34                                             1-piperazinyl]ethyl]cyclohexanol                                              (mixture of cis/trans)                                                   7    1-(4-Fluorophenyl)-4-[2-[4-(2-                                                                    94% inhibition                                                                         0.64      48% inhibition                                                                          16.5                         pyridinyl)-1-piperazinyl]ethyl]-                                                                  at 10.sup.-5 M                                            cyclohexanol (mixture of cis/trans)                                      8    cis-1-(4-Methoxyphenyl)-4-[2-[4-(2-                                                               169      0.9       88% inhibition                         pyridinyl)-1-piperazinyl]ethyl]-                                              cyclohexanol                                                             9    4-[2-[4-(2-Pyridinyl)-1-piperazinyl]-                                                             1550     1.0                                              ethyl]-1-(2-thiazolyl)cyclohexanol                                            (mixture of cis/trans)                                                  10    1-(3-Pyridinyl)-4-[2-[4-(2-pyridinyl)-                                                            847      0.37                                             1-piperazinyl]ethyl]cyclohexanol                                              (mixture of cis/trans)                                                  11    cis-1-(2-Pyridinyl)-4-[2-[3,6-dihydro-                                                            156      0.64                3.5                          4-phenyl-1(2H)-pyridinyl]ethyl]cyclo-                                         hexanol                                                                 12    cis-1-(3-Pyridinyl)-4-[2-[3,6-dihydro-                                                            116      0.25      79% inhibition                         4-phenyl-1(2H)-pyridinyl]ethyl]cyclo-                                         hexanol                                                                 13    cis-4-[2-(3,6-Dihydro-4-phenyl-1(2H)-                                                              51      2                                                pyridinyl)ethyl]-1-(2-thienyl)cyclo-                                          hexanol                                                                 14    4-[2-[4-(2-Pyridinyl)-1-piperazinyl]-                                                             312      0.48      37% inhibition                                                                          4.5                          ethyl]-1-(3-thienyl)cyclohexanol                                              (mixture of cis/trans)                                                  15    trans-1-(4-Methoxyphenyl)-4-[2-[4-                                                                932      0.3       52% inhibition                         (2-pyridinyl)-1-piperazinyl]ethyl]-                                           cyclohexanol                                                            16    trans-4-[[4-(2-Pyridinyl)-1-piperazinyl]-                                                                  4.3                                              methyl]-1-(2-thienyl)cyclohexanol                                       17    cis-4-[[4-(2-Pyridinyl)-1-piperazinyl]-                                                           3900     5.2                                              methyl]-1-(2-thienyl)cyclohexanol                                       18    trans-1-(2-Pyridinyl)-4-[4-(2-                                                                             >30                                              pyrimidinyl)-1-piperazinyl]cyclohexanol                                 19    cis-1-(2-Pyridinyl)-4-[4-(2-pyrimidinyl)-                                                                  13.0                                             1-piperazinyl]cyclohexanol                                              20    trans-1-(2-Pyridinyl)-4-[4-(2-pyridinyl)-                                                                  >30                                              1-piperazinyl]cyclohexanol                                              21    cis-1-(2-Pyridinyl)-4-[4-(2-pyridinyl)-                                                           2785     2.3                                              1-piperazinyl]cyclohexanol                                              22    trans-1-(3-Pyridinyl)-4-[4-(2-pyridinyl)-                                                         12500    30                                               1-piperazinyl]cyclohexanol                                              23    cis-1-(3-Pyridinyl)-4-[4-(2-pyridinyl)-                                                           1155     1.6                                              1-piperazinyl]cyclohexanol                                              24    4-[4-(2-Pyridinyl)-1-piperazinyl]-1-                                                                       >30                                              (2-thienyl)cyclohexanol (mixture of                                           cis/trans)                                                              25    4-[4-(2-Pyridinyl)-1-piperazinyl]-1-                                                              2700     2.4                                              (3-thienyl)cyclohexanol (mixture of                                           cis/trans)                                                              26    1-(4-Methoxyphenyl)-4-[4-(2-pyridinyl)-                                                           670      0.3                                              1-piperazinyl]cyclohexanol (mixture of                                        cis/trans)                                                              27    1-Phenyl-4-[4-(2-pyridinyl)-1-                                                                    1660     0.83                                             piperazinyl]cyclohexanol (mixture of                                          cis/trans)                                                              28    4-(3,6-Dihydro-4-phenyl-1(2H)-                                                                             1.8                                              pyridinyl)-1-(2-pyridinyl)cyclohexanol                                        (mixture of cis/trans)                                                  29    trans-4-(3,6-Dihydro-4-phenyl-1(2H)-                                                                       25.6                                             pyridinyl)-1-(3-pyridinyl)cyclohexanol                                  30    cis-4-(3,6-Dihydro-4-phenyl-1(2H)-                                                                1250     1.3                                              pyridinyl)-1-(3-pyridinyl)cyclohexanol                                  40    trans N-[4-[4-(2-Pyridinyl)-1-                                                                    2800     0.36      65% inhibition                         piperazinyl]cyclohexyl]benzamide                                        41    trans N-[4-[4-(2-Pyridinyl)-1-                                                                    530      1.9                                              piperazinyl]cyclohexyl]-2-methoxy-                                            benzamide                                                               42    trans N-Methyl-N-[4-[4-(2-pyridinyl)-1-                                                           4840     2.4       15% inhibition                         piperazinyl]cyclohexyl]-benzamide                                       43    trans 4-Chloro-N-[4-[4-(2-pyridinyl)-1-                                                           7790     0.78                                             piperazinyl]cyclohexyl]benzamide                                        44    trans N-[4-[4-(2-Pyridinyl)-1-                                                                    2520     0.29                                             piperazinyl]cyclohexyl]-2-                                                    thiophenecarboxamide                                                    46    trans N-[4-(3,6-Dihydro-4-phenyl-1(2H)-                                                           360      0.16      95% inhibition                         pyridinyl)cyclohexyl]benzamide                                          47    trans N-[4-(3,6-Dihydro-4-phenyl-1(2H)-                                                           300      0.23      74% inhibition                         pyridinyl)cyclohexyl]-2-thiophene-                                            carboxamide                                                             48    trans N-[4-(3,6-Dihydro-4-phenyl-1(2H)-                                                            90      0.27      88% inhibition                         pyridinyl)cyclohexyl]-3-thiophenecarbox-                                      amide                                                                   49    trans N-[4-(3,6-Dihydro-4-phenyl-1(2H)-                                                           600      2.4       72% inhibition                         pyridinyl)-cyclohexyl]-3-pyridine-                                            carboxamide                                                             50    trans N-[4-(3,6-Dihydro-4-phenyl-1(2H)-                                                           1600     1.1                                              pyridinyl)cyclohexyl]cyclohexane-                                             carboxamide                                                             52    trans N-[4-[2-[4-(2-Pyridinyl)-1-                                                                 440      0.16      87% inhibition                         piperazinyl]ethyl]cyclohexyl]benzamide                                  53    cis N-[4-[2-[4-(2-Pyridinyl)-1-                                                                   3280     4.5       36% inhibition                         piperazinyl]ethyl]cyclohexyl]benzamide                                  54    trans 4-Methyl-N-[4-[2-[4-(2-pyridinyl)-                                                          290      0.11       0% inhibition                         1-piperazinyl]ethyl]cyclohexyl]benzamide                                55    cis 4-Methyl-N-[4-[2-[4-(2-pyridinyl)-                                                            830                                                       1-piperazinyl]ethyl]cyclohexyl]-                                              benzamide                                                               56    cis 4-Chloro-N-[4-[2-[4-(2-pyridinyl)-                                                            1620     6.30                                             1-piperazinyl]ethyl]cyclohexyl]-                                              benzamide                                                               57    trans 4-Chloro-N-[4-[2-[4-(2-pyridinyl)-                                                          620      0.51                                             1-piperazinyl]ethyl]cyclohexyl]-                                              benzamide                                                               58    trans N-[4-[2-[4-(2-Pyridinyl)-1-                                                                          0.03      87% inhibition                         piperazinyl]ethyl]cyclohexyl]acetamide                                  59    trans 3,4-Dichloro-N-[4-[2-[4-(2-                                                                          14.4       7% inhibition                         pyridinyl)-1-piperazinyl]ethyl]-                                              cyclohexyl]benzamide                                                    60    trans N-[4-[[4-(2-Pyridinyl)-1-                                                                            1.0       36% inhibition                         piperazinyl]methyl]cyclohexyl]-                                               benzamide                                                               69    cis N-[4-[2-(3,6-Dihydro-4-phenyl-                                                                         2.1                                              1(2H)-pyridinyl)ethyl]cyclohexyl]-                                            benzamide                                                               70    cis N-[4-[2-(3,6-Dihydro-4-phenyl-                                                                280                                                       1(2H)-pyridinyl)ethyl]cyclohexyl]-2-                                          thiophenecarboxamide                                                    71    trans N-[4-[2-(3,6-Dihydro-4-phenyl-                                                              210      0.21      79% inhibition                         1(2H)-pyridinyl)ethyl]cyclohexyl]-2-                                          thiophenecarboxamide                                                    72    trans N-[4-[2-(3,6-Dihydro-4-phenyl-                                                              100      0.27      74% inhibition                         1(2H)-pyridinyl)ethyl]cyclohexyl]-                                            benzamide                                                               73    trans N-[4-[2-[4-(2-Pyridinyl)-1-                                                                 220      0.09      86% inhibition                         piperazinyl]ethyl]cyclohexyl]-2-                                              thiophenecarboxamide                                                    74    cis N-[4-[2-[4-(2-Pyridinyl)-1-                                                                   1460     1.6       51% inhibition                         piperazinyl]ethyl]cyclohexyl]-2-                                              thiophenecarboxamide                                                    __________________________________________________________________________

A compound of Formula Ia ##STR19## wherein R is --OH, ##STR20## whereinR⁴ is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aryllower alkyl, lower alkanoyl, cycloalkanoyl, cycloalkylalkanoyl, aryllower alkanoyl, or aroyl, ##STR21## wherein R⁴ is hydrogen, lower alkyl,cycloalkyl, cycloalkylalkyl, aryl, aryl lower alkyl, lower alkanoyl,aryl lower alkanoyl, or aroyl;

m is zero or an integer from 1 to 2;

R is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl or2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, lower alkoxy, orhalogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, loweralkoxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl substituted bylower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl substitutedby lower alkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, or5-thiazolyl substituted by lower alkyl or halogen;

n is zero or an integer from 1 to 4;

R² is ##STR22## wherein R⁷ is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-,4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by loweralkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2-or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl orhalogen; and the corresponding cis and trans isomers thereof; or apharmaceutically acceptable acid addition salt thereof may be preparedby reacting a compound of Formula II ##STR23## wherein A is O, N--R⁴wherein R⁴ is as defined above, or N--OR⁴ wherein R⁴ is as definedabove,

and R² and n are as defined above with a compound of Formula III##STR24## wherein M is magnesium-Hal, wherein Hal is halogen or M islithium and R¹ and m are as defined above, in the presence of a solventsuch as, for example, tetrahydrofuran, diethyl ether, and the like atabout --78° C. to about the reflux temperature of the solvent for about0.5 to about 24 hours to give a compound of Formula Ia.

A compound of Formula Ib ##STR25## wherein R^(a) is --OR³, wherein R³ islower alkyl, cycloalkyl, cycloalkylalkyl, or aryl lower alkyl;

m is zero or an integer from 1 to 2;

R¹ is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl or2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, lower alkoxy, orhalogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, loweralkoxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl substituted bylower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl substitutedby lower alkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, or5-thiazolyl substituted by lower alkyl or halogen;

n is zero or an integer from 1 to 4;

R² is ##STR26## wherein R⁷ is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-,4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by loweralkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2-or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl orhalogen; and the corresponding cis and trans isomers thereof; or apharmaceutically acceptable acid addition salt thereof may be preparedby reacting a compound of Formula Ic ##STR27## wherein R¹, m, n, and R²are as defined above with a compound of Formula IV

    R.sup.3 -Hal                                               IV

wherein Hal is halogen and R³ is as defined above in the presence of abase such as an organic base, for example, triethylamine, pyridine andthe like, an inorganic base, for example, an alkali metal or alkalineearth metal hydroxide or carbonate, alkali metal hydride and the likeand a solvent such as, for example, dichloromethane, and the like atabout -78° C. to about the reflux temperature of the solvent for about0.5 to about 24 hours to give a compound of Formula Ib.

A compound of Formula Id ##STR28## wherein R^(b) is --OR³.spsp.a,wherein R³.spsp.a is lower alkanoyl, aroyl, or aryl lower alkanoyl;

m is zero or an integer from 1 to 2;

R¹ is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl or2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, lower alkoxy, orhalogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, loweralkoxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl substituted bylower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl substitutedby lower alkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, or5-thiazolyl substituted by lower alkyl or halogen;

n is zero or an integer from 1 to 4;

R² is ##STR29## wherein R⁷ is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-,4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by loweralkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2-or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl orhalogen; and the corresponding cis and trans isomers thereof; or apharmaceutically acceptable acid addition salt thereof may be preparedby reacting a compound of Formula Ic with a compound of Formula V

    R.sup.3.spsp.a -Hal                                        V

wherein Hal is halogen and R³.spsp.a is as defined above using themethodology used to prepare a compound of Formula Ib from a compound ofFormula Ic and a compound of Formula IV to give a compound of FormulaId.

A compound of Formula Ie ##STR30## wherein R^(c) is ##STR31## wherein R⁴and R⁵ are each independently hydrogen, lower alkyl, cycloalkyl,cycloalkylalkyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl loweralkyl, lower alkanoyl, aryl lower alkanoyl, heteroaryl lower alkanoyl,aroyl, heteroaroyl, or R⁴ and R⁵ are taken together with the nitrogenatom to which they are attached to form a ring denoted by wherein p iszero or an integer from 1 to 4 and R⁶ is hydrogen, lower alkyl,cycloalkyl, or cycloalkylalkyl, ##STR32## wherein X is oxygen or sulfuror ##STR33## wherein R⁶ is as defined above, or ##STR34## wherein R⁴ andR⁵ are each independently hydrogen, lower alkyl, cycloalkyl,cycloalkylalkyl, aryl, aryl lower alkyl, lower alkanoyl, aryl loweralkanoyl, aroyl, or R⁴ and R⁵ are taken together with the oxygen andnitrogen atoms to which they are attached to form a ring denoted by##STR35## wherein q is an integer from 2 to 3 and R⁶ is as definedabove; m is zero or an integer from 1 to 2;

R¹ is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl or2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, lower alkoxy, orhalogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, loweralkoxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl substituted bylower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl substitutedby lower alkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, or5-thiazolyl substituted by lower alkyl or halogen;

n is zero or an integer from 1 to 4;

R² is ##STR36## wherein R⁷ is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-,4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by loweralkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2-or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl orhalogen; and the corresponding cis and trans isomers thereof; or apharmaceutically acceptable acid addition salt thereof may be preparedby reacting a compound of Formula VI ##STR37## wherein R^(c), R², and nare as defined above with a compound of Formula III wherein M, R¹, and mare as defined above in the presence of a solvent such as, for example,tetrahydrofuran and the like at about 0° C. for about 0.5 to about 24hours to give a compound of Formula Ie.

A compound of Formula If ##STR38## wherein n is zero or an integer from1 to 4;

R₂ is ##STR39## wherein R⁷ is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-,4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by loweralkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2-or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl orhalogen; and the corresponding cis and trans isomers thereof; or apharmaceutically acceptable acid addition salt thereof may be preparedby reacting a compound of Formula IIb ##STR40## wherein R² and n are asdefined above with a metal hydride such as, for example, lithiumaluminum hydride and the like and a solvent such as, for example,tetrahydrofuran and the like or alternatively treating with hydrogen inthe presence of a catalyst such as a noble metal, for example, platinum,palladium, rhodium, ruthenium, derivatives thereof, and the like to giveabout 1:1 mixture of the cis and trans isomers of a compound of FormulaIf which if desired may be separated into the individual cis or transisomers by conventional methodology such as, for example, by fractionalcrystallization, chromatography and the like.

A compound of Formula Ig ##STR41## wherein R⁴.spsp. a is lower alkyl,cycloalkyl, cycloalkylalkyl, aryl lower alkyl, heteroaryl lower alkyl,aryl or heteroaryl;

n is zero or an integer from one to four;

R² is ##STR42## wherein R⁷ is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-,4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by loweralkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2-or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl orhalogen; and the corresponding cis and trans isomers thereof; or apharmaceutically acceptable acid addition salt thereof may be preparedby reacting a compound of Formula If with a compound of Formula XIX##STR43## wherein L is halogen or a leaving group such as, for example,CH₃ SO₂ O-, para-CH₃ C₆ H₄ SO₂ O-, and the like and R⁴.spsp.a is asdefined above in the presence of a base such as, for example,triethylamine, pyridine and the like and a solvent such as, for example,dichloromethane and the like to give a compound of Formula Ig.

A compound of Formula Ih ##STR44## wherein R⁴.spsp.a is lower alkyl,cycloalkyl, cycloalkylalkyl, aryl lower alkyl, heteroaryl lower alkyl,aryl or heteroaryl;

R⁵.spsp.a is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl,aryl lower alkyl or heteroaryl lower alkyl; n is zero or an integer fromone to four;

R² is ##STR45## wherein R⁷ is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or4- pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-,4-, or 5-pyrimidinyl or 2-, 4-, or 5- pyrimidinyl substituted by loweralkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2-or 3- furanyl substituted by lower alkyl or halogen, 2-, 4-, or5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl orhalogen; and the corresponding cis and trans isomers thereof; or apharmaceutically acceptable acid addition salt thereof may be preparedby reacting a compound of Formula Ig with a compound of Formula XX

    R.sup.5.spsp.a -Hal                                        XX

wherein Hal is halogen and R⁵.spsp.a is as defined above in the presenceof a metal hydride such as, for example, sodium hydride and the like anda solvent such as, for example, tetrahydrofuran, dimethylformamide andthe like to give a compound of Formula Ih.

A compound of Formula Ii ##STR46## R⁴.spsp.a is lower alkyl, cycloalkyl,cycloalkylalkyl, aryl lower alkyl, heteroaryl lower alkyl, aryl, orheteroaryl;

n is zero or an integer from 1 to 4;

R² is ##STR47## wherein R⁷ is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-,4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by loweralkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2-or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl orhalogen; and the corresponding cis and trans isomers thereof; or apharmaceutically acceptable acid addition salt thereof may be preparedby reacting a compound of Formula Ig with a compound of Formula XIXusing the methodology used to prepare a compound of Formula If to give acompound of Formula Ii.

A compound for Formula Ij ##STR48## wherein R⁵.spsp.a is lower alkyl,cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aryl lower alkyl orheteroaryl lower alkyl; n is zero or an integer from one to four;

R² is ##STR49## wherein R⁷ is aryl, 2-, 3-, or 4- pyridinyl or 2-, 3-,or 4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-,4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by loweralkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2-or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl orhalogen; and the corresponding cis and trans isomers thereof; or apharmaceutically acceptable acid addition salt thereof may be preparedby reacting a compound of Formula IIc ##STR50## wherein A^(b) isN-R⁵.spsp.a, and R⁵.spsp.a, n and R² are defined above in the presenceof a metal hydride such as, for example, lithium aluminum hydride,sodium borohydride and the like to give a compound of Formula Ij.

Alternatively, a compound of Formula Ih may be prepared from a compoundof Formula Ij by reacting with a compound of Formula XIX using themethodology used to prepare a compound of Formula Ig.

A compound of Formula VI is prepared from a compound of Formula IIa##STR51## wherein R² and n are as defined above and a compound ofFormula VII

    R.sup.c H                                                  VII

wherein R^(c) is as defined above in the presence of an alkali metalcyanide such as, for example, potassium cyanide and the like and aboutan equivalent of an acid such as an organic acid, for example, aceticacid and the like, an inorganic acid, for example, hydrochloric acid andthe like, in the presence of a solvent such as, for example, methanol,ethanol and the like at about room temperature to give a compound ofFormula VI.

A compound of Formula IIa is prepared from a compound of Formula VIII##STR52## wherein R⁸ and R⁹ are alkyl of one to six carbon atoms or R⁸and R⁹ together are ##STR53## --CH₂ CH₂ -- or --CH₂ CH₂ CH₂ -- and R²and n are as defined above by treatment with an acid such as, forexample, a 10% aqueous solution of hydrochloric acid in the presence ofa solvent such as, for example, acetone and the like to give a compoundof Formula IIa.

A compound of Formula VIIIa ##STR54## wherein n is zero and R², R⁸, andR⁹ are as defined above is prepared from a compound of Formula IX##STR55## wherein R², R⁸, and R⁹ are as defined above by treatment witha reducing agent such as, for example, sodium cyanoborohydride and thelike in a solvent such as, for example, methanol and the like in thepresence of an acid such as, for example, hydrochloric acid and the likeor, alternatively, reduction is carried out with hydrogen in thepresence of a catalyst such as, for example, palladium on carbon in thepresence of a solvent such as, for example, methanol and the like togive a compound of Formula VIIIa.

A compound of Formula IX is prepared from a compound of Formula X##STR56## wherein R⁸ and R⁹ are as defined above in the presence of acatalytic amount of an acid such as, for example, para-toluenesulfonicacid and the like in the presence of a solvent suited for the azeotropicremoval of water such as, for example, toluene and the like to give acompound of Formula IX.

A compound of Formula VIIIb wherein n is an integer from 1 to 4 and R²,R⁸, and R⁹ are as defined above is prepared from a compound of FormulaXI ##STR57## wherein n is an integer from 1 to 4 and R², R⁸, and R⁹ areas defined above by treatment with a reducing agent such as, forexample, diborane, aluminum hydride and the like in a solvent such as,for example, tetrahydrofuran and the like to give a compound of FormulaVIIIb.

A compound of Formula XI is prepared from a compound of Formula XII##STR58## wherein n is an integer from 1 to 4 and R⁸ and R⁹ are asdefined above and a compound of Formula XI. In order to obtain thereaction of these two compounds, a compound of Formula XII must beactivated in the presence of a chloroformate such as, for example,isobutyl chloroformate and a base such as, for example, triethylamine,or alternatively, a coupling reagent such as, for example,dicyclohexylcarbodiimide, carbonyldiimidazole and the like in thepresence of a solvent such as, for example, dichloromethane and the liketo give a compound of Formula XI.

A compound of Formula XII is prepared from a compound of Formula XIII##STR59## wherein n is an integer from 1 to 4, R¹⁰ is lower alkyl and R⁸and R⁹ are as defined above, by hydrolysis with a base such as, forexample, potassium hydroxide and the like in an alcohol such as, forexample, ethanol and the like to give a compound of Formula XII.

A compound of Formula XIII is prepared from a compound of Formula XIV##STR60## wherein n is an integer from 1 to 4 and R¹⁰ is as definedabove using conventional procedures known in the art.

Alternatively, a compound of Formula VIIIb is prepared from a compoundof Formula XV ##STR61## wherein n is an integer from 1 to 4, L ishalogen, CH₃ SO₂ O--, para--CH₃ C₆ H₄ SO₂ O--and the like, and R⁸ and R⁹are as defined above and a compound of Formula XVI

    R.sup.2 H                                                  XVI

wherein R² is as defined above in the presence of a base such as, forexample, sodium bicarbonate and the like and a solvent such as, forexample, dimethylformamide and the like to give a compound of FormulaVIIIb.

A compound of Formula XV is prepared from a compound of Formula XVII##STR62## wherein n is an integer from 1 to 4 and R⁸ and R⁹ are asdefined above by treatment with thionyl chloride, thionyl bromide andthe like in the presence of a solvent such as, for example, chloroformand the like or, alternatively, treatment with methanesulfonyl chloride,para-toluenesulfonyl chloride and the like in the presence of a basesuch as, for example, pyridine and the like to give a compound ofFormula XV.

A compound of Formula XVII is prepared from a compound of Formula XIVwherein n is an integer from 1 to 4 and R⁸, R⁹, and R¹⁰ are as definedabove by treatment with a complex metal hydride such as, for example,diborane, lithium aluminum hydride and the like in the presence of asolvent such as, for example, tetrahydrofuran and the like to give acompound of Formula XVII.

A compound of Formula IId ##STR63## wherein A^(a) is N--R⁴ wherein R⁴ isas defined above, or

N--OR⁴ wherein R⁴ is as defined above and R² and n are as defined aboveis prepared from a compound of Formula IIa and a compound of FormulaXVIII

    A.sup.a H                                                  XVIII

wherein A^(a) is ##STR64## wherein R⁴ is as defined above, or ##STR65##wherein R⁴ is as defined above, in the presence of an acid such as, forexample, para-toluenesulfonic acid to give a compound of Formula IId.

Compounds of Formula III, Formula IV, Formula V, Formula VII, Formula X,Formula XI, Formula XIV, Formula XVIII, Formula XIX and Formula XX areeither known or capable of being prepared by methods known in the art.

A compound of Formula I may exist as a mixture of cis or trans isomersor as the separate cis or trans isomer. Accordingly, as another aspectof the present invention, a mixture of cis and trans isomers of FormulaI may be separated into the individual cis or trans isomer byconventional methodology such as, for example, by fractionalcrystallization, chromatography and the like.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. It will beobvious to those skilled in the art that the following dosage forms maycomprise as the active component, either a compound of Formula I or acorresponding pharmaceutically acceptable salt of a compound of FormulaI.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 1 mg to 1000 mg preferably 10 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as antipsychotic agents, the compounds utilized inthe pharmaceutical method of this invention are administered at theinitial dosage of about 1 mg to about 50 mg per kilogram daily. A dailydose range of about 5 mg to about 25 mg per kilogram is preferred. Thedosages, however, may be varied depending upon the requirements of thepatient, the severity of the condition being treated, and the compoundbeing employed. Determination of the proper dosage for a particularsituation is within the skill of the art. Generally, treatment isinitiated with smaller dosages which are less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. Forconvenience, the total daily dosage may be divided and administered inportions during the day if desired.

The following nonlimiting examples illustrate the inventors' preferredmethods for preparing the compounds of the invention.

EXAMPLE 1 AND EXAMPLE 1a

cis- andtrans-1-(4-Chlorophenyl)-4-[4-(2-pyridinyl)-1piperazinyl]cyclohexanol.

A solution of 5.74 g of 1-bromo-4-chlorobenzene in 100 mL anhydroustetrahydrofuran is cooled to -78° C. under a nitrogen atmosphere.n-Butyllithium (18.75 mL of a 1.6M hexane solution) is added dropwisevia syringe. The resulting suspension is stirred at -78° C. for 1 hour.To this solution is added a solution of 5.19 g of4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanone (Example A) in 175 mL oftetrahydrofuran from an addition funnel. The addition of the ketonetakes about 15 minutes. The mixture is allowed to warm to roomtemperature and quenched with 50 mL of saturated ammonium chloridesolution. The tetrahydrofuran is evaporated under vacuum and the residueis partitioned into water/dichloromethane. The organic phase isseparated, dried over magnesium sulfate, and evaporated in vacuo. Theresidue is chromatographed on silica gel using 3% methanol:97%dichloromethane as eluant. The less polar isomer in this solvent systemis characterized as trans-1-(4-chlorophenyl)-4-[4 (2-pyridinyl)-1-piperazinyl]cyclohexanol containing 0.15 molecules of chloroform; mp224-225° C (Example 1) and the more polar component is identified ascis-1(4-chlorophenyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol; mp183-185° C. (Example 1a).

In a process analogous to Example 1 and Example 1a using appropriatestarting materials the corresponding compounds of Formula I (Examples 2to 30) are prepared as follows:

EXAMPLE 2

4-[2-4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thienyl)cyclohexanol(mixture of cis/trans), containing 0.33 molecules of chloroform; mp124-140° C.

EXAMPLE 3

cis-4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thienyl)cyclohexanol,hemihydrate; mp 151-154° C.

EXAMPLE 4

trans-4-2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thienyl)cyclohexanol;mp 108-109° C.

EXAMPLE 5

1-Phenyl-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol (mixtureof cis/trans), containing 0.1 molecules of water; mp 158-163° C.

EXAMPLE 6

1-(2-Pyridinyl)-4-2-4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol(mixture of cis/trans), containing 0.25 molecules of water; mp 100-105°C.

EXAMPLE 7

1-(4-Fluorophenyl)-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol(mixture of cis/trans); mp 172-177° C.

EXAMPLE 8

cis-1-(4-Methoxyphenyl)-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol,containing 0.2 molecules of water; mp 142-144° C.

EXAMPLE 9

4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(2-thiazolyl)cyclohexanol(mixture of cis/trans), containing 0.75 molecules of chloroform; mp65-80° C.

EXAMPLE 10

1-(3-Pyridinyl)-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexanol(mixture of cis/trans), containing 0.2 molecules of water; mp 128-148°C.

EXAMPLE 11

cis-1-(2-Pyridinyl)-4-[2-[3,6-dihydro-4-phenyl-(2H)-pyridinyl]ethyl]cyclohexanol;mp 153-156° C.

EXAMPLE 12

cis-1-(3-Pyridinyl)-4-[2-[3,6-dihydro-4-phenyl-(2H)-pyridinyl]ethyl]cyclohexanol;mp 160-163° C.

EXAMPLE 13

cis-4-[2-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-ethyl]-1-(2-thienyl)cyclohexanol,containing 0.1 molecules of water; mp 164-170° C.

EXAMPLE 14

4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-1-(3)thienyl)cyclohexanol(mixture of cis/trans), containing 0.2 molecules of water; mp 115-129°C.

EXAMPLE 15

trans-1-(4-Methoxyphenyl)-4-[2-[4-(2-pyridinyl)-1piperazinyl]ethyl]cyclohexanol,containing 0.2 molecules of water; mp 127-131° C.

EXAMPLE 16

trans-4-[[4-(2-Pyridinyl)-1-piperazinyl]methyl]-1-(2-thienyl)cyclohexanol;mp 50-52° C.

EXAMPLE 17

cis-4-[[4-(2-Pyridinyl)-1-piperazinyl]methyl]-1-2-thienyl)cyclohexanol,trihydrochloride, containing 2.5 molecules of water; mp 114-117° C.

EXAMPLE 18

trans-1-(2-Pyridinyl)-4-[4-(2-pyrimidinyl)-1-piperazinyl]cyclohexanol;mp 240-242° C.

EXAMPLE 19

cis-1-(2-Pyridinyl)-4-[4-(2-pyrimidinyl)-1-piperazinyl]cyclohexanol,trihydrochloride, containing 3.5 molecules of water; mp 138-140° C.

EXAMPLE 20

trans-1-(2-Pyridinyl)-4-4-(2-pyridinyl)-1-piperazinyl]cyclohexanol,containing 0.25 molecules of water; mp 86-93° C.

EXAMPLE 21

cis-1-(2-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]-cyclohexanol,containing 0.4 molecules of water; mp 130-134° C.

EXAMPLE 22

trans-1-(3-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol; mp153-158° C.

EXAMPLE 23

cis-1-(3-Pyridinyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol,hemihydrate; mp 175-179° C.

EXAMPLE 24

4-[4-(2-Pyridinyl)-1-piperazinyl]-1-(2-thienyl)cyclohexanol (mixture ofcis/trans); mp 130-135° C.

EXAMPLE 25

4-[4-(2-Pyridinyl)-1-piperazinyl]-1-(3-thienyl)cyclohexanol (mixture ofcis/trans); mp 140-155° C.

EXAMPLE 26

1-(4-Methoxyphenyl)-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanol(mixture of cis/trans); mp 154-157° C.

EXAMPLE 27

1-Phenyl-4-[4-(2-pyridinyl)-1-piperazinylcyclohexanol (mixture ofcis/trans), containing 0.25 molecules of water; mp 164-172° C.

EXAMPLE 28

4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(2-pyridinyl)cyclohexanol(mixture of cis/trans); mp 157-159° C.

EXAMPLE 29

trans-4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-1-(3-pyridinyl)cyclohexanol;mp 124-125° C.

EXAMPLE 30

cis-4-[3,6-Dihydro-4-phenyl-1(2H)-pyridinyl]-1-(3-pyridinyl)cyclohexanol;mp 199-200° C.

EXAMPLE 31 AND 31a

(cis) and (trans)-4-[4-(2-Pyridinyl)-1-piperazinyl]cyclohexylamine

A suspension of 15.0 g of 4-[4-(2-pyridinyl)-1piperazinyl]cyclohexanoneoxime (Example B) in 300 mL of dry tetrahydrofuran is cooled in an icebath. To this suspension, 5.7 g of lithium aluminum hydride is added insmall portions over a period of 30 minutes. The reaction mixture isheated at reflux for 2 hours. The flask is cooled in an ice bath and thereaction is quenched by careful addition of 6 mL of water, followed by 6mL of 15% sodium hydroxide solution in water, and finally 12 mL ofwater. The salts are filtered through celite and washed repeatedly withdichloromethane. The pooled filtrates are dried over magnesium sulfateand evaporated in vacuo to leave 15 g of a semisolid residue thatconsists of about equal amounts of cis- andtrans-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexylamine. The isomers areseparated by medium pressure liquid chromatography(MPLC):cis-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexylamine, mp 120-125°C. (Example 31).

trans-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexylamine, mp>250° C.(Example 31a).

In a process analogous to Example 31 and Example 31a using appropriatestarting materials the corresponding compound of Formula I (Examples 32to 38) are prepared as follows:

EXAMPLE 32

cis-4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl amine, mp97.7-98.7° C.

EXAMPLE 33

trans-4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl) cyclohexylamine; mp105.6-106.5° C.

EXAMPLE 34

cis- and trans-4-[[4-(2-Pyridinyl)-1-piperazinyl]methyl]cyclohexylamine

EXAMPLE 35

cis-4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexylamine; mp 78-79°C.

EXAMPLE 36

trans-4-2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexylamine; mp82-84° C.

EXAMPLE 37

cis- andtrans-4-[2-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)ethyl]cyclohexylamine.

EXAMPLE 38

cis- andtrans-4-[2-[3,6-Dihydro-4-(2-pyridinyl)-(2H)-pyridinyl]ethyl]cyclohexylamine.

EXAMPLE 39

trans-N-4-[4-(2-Pyridinyl)-1-piperazinyl]cyclohexyl]benzamide

To a solution of 5.8 gtrans-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexylamine (Example 31a) in100 mL of dichloromethane is added 4 mL of triethylamine and 2.84 mL ofbenzoyl chloride. The reaction mixture is refluxed under nitrogen for 1hour. Saturated sodium bicarbonate solution is added. Some of theproduct comes out of solution at this point and is isolated byfiltration. The organic layer is dried and evaporated to give 5.2 g oftrans-N-[4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexyl]benzamide; mp241-244° C.

In a process analogous to Example 39 using appropriate startingmaterials, the corresponding compounds of Formula I are prepared. Incertain examples a mixture of cis and trans isomers are used as startingmaterial and the corresponding cis and trans isomers of Formula I can beseparated by MPLC eluting with 3% methanol in dichloromethane or byfractional crystallization. Thus, Example 40 to 74 are prepared asfollows:

EXAMPLE 40

trans N-[4-[4-(2-Pyridinyl)-1-piperazinyl]cyclohexyl]-benzamide; mp241-244° C.

EXAMPLE 41

transN-[4-[4-(2-Pyridinyl)-1-piperazinyl]-cyclohexyl]-2-methoxybenzamide; mp128-133° C.

EXAMPLE 42

trans N-Methyl-N-[4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexyl]benzamide;mp 176-179° C.

EXAMPLE 43

trans 4-Chloro-N-[4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexyl]benzamide;mp 281-284° C.

EXAMPLE 44

transN-[4-[4-(2-Pyridinyl)-1-piperazinyl]cyclohexyl]-2-thiophenecarboxamide;mp 255-258° C.

EXAMPLE 45

transN-[4-[4-(2-Pyridinyl)-1-piperazinyl]cyclohexyl]-3-thiophenecarboxamide;mp 250-256° C.

EXAMPLE 46

N-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)-cyclohexyl]benzamide; mp238-240° C.

EXAMPLE 47

transN-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]-2-thiophenecarboxamide;mp 221-222° C.

EXAMPLE 48

transN-[4-(3,6-Dihydro-4-phenyl-1(2H)-Pyridinyl)cyclohexyl]-3-thiophenecarboxamide;mp 236.5-237.8° C.

EXAMPLE 49

transN-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]-3-pyridinecarboxamide;mp 230-231° C.

EXAMPLE 50

transN-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]cyclohexanecarboxamide;mp 220-221° C.

EXAMPLE 51

trans 4-Methyl-N-4-[4-(2-pyridinyl-1-piperazinyl]cyclohexyl]benzamide;mp 240-242° C.

EXAMPLE 52

trans N-[4-[2-[4-(2-Pyridinyl-1-piperazinyl ethyl]cyclohexyl]benzamide;mp 206-210° C.

EXAMPLE 53

cis N-[4-[2-[4-(2-Pyridinyl-1-piperazinyl]ethyl]cyclohexyl]benzamide; mp150-154° C.

EXAMPLE 54

trans4-Methyl-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;mp 220-223° C.

EXAMPLE 55

cis4-Methyl-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;mp 153-155° C.

EXAMPLE 56

cis 4-Chloro-N-[4-[2-[4-(2-pyridinyl)-1-piperazinylethyl]cyclohexyl]benzamide; mp 149-151° C.

EXAMPLE 57

trans4-Chloro-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;mp 228-231° C.

EXAMPLE 58

trans N-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]acetamide;mp 188-190° C.

EXAMPLE 59

trans3,4-Dichloro-N-[4-2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;mp 219-221° C.

EXAMPLE 60

trans N-[4-[[4-(2-Pyridinyl)-1-piperazinyl]methyl]cyclohexyl]benzamide;mp 206-208° C.

EXAMPLE 61

cis3,4-Dichloro-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;mp 151-153° C.

EXAMPLE 62

trans4-Chloro-N-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]benzamide;mp 260-261° C.

EXAMPLE 63

trans N-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]-4-fluorobenzamide; mp 235-236° C.

EXAMPLE 64

trans N-[4-[[4-(2-Pyridinyl)-1-piperazinyl]methyl]cyclohexyl]-3thiophenecarboxamide; mp 201-203° C.

EXAMPLE 65

trans4-Methoxy-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;mp 215-217° C.

EXAMPLE 66

cis-N-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]-3-thiophenecarboxamide;mp 188-200° C.

EXAMPLE 67

cis-N-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]-2-furancarboxamide;mp 140-143° C.

EXAMPLE 68

cis-4-Methoxy-N-4-[2-4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;mp 125-130° C.

EXAMPLE 69

cisN-[4-[2-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)ethyl]cyclohexyl]benzamide;mp 130-133° C.

EXAMPLE 70

cisN-[4-[2-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)ethyl]cyclohexyl]-2-thiophenecarboxamide;mp 122-124° C.

EXAMPLE 71

transN-[4-[2-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)ethyl]cyclohexyl-2-thiophenecarboxamide;mp 211-215° C.

EXAMPLE 72

transN-[4-[2-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)ethyl]cyclohexyl]benzamide;mp 219-224° C.

EXAMPLE 73

trans N-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethylcyclohexyl]-2-thiophenecarboxamide; mp 207-208° C.

EXAMPLE 74

cisN-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]-2-thiophenecarboxamide;mp 187-189° C.

PREPARATION OF STARTING MATERIALS EXAMPLE A

4-4-(2-Pyridinyl)-1-piperazinyl]cyclohexanone.

A solution of 1,4-cyclohexanedione monoethyleneketal (50.0 g),1-(2-pyridyl)piperazine (52.16 g), and p-toluenesulfonic acid (0.5 g) in500 ml of toluene is refluxed with a Dean-Stark trap until thetheoretical amount of water is collected (about four hours). The solventis evaporated in vacuo and the residue is dissolved in 750 mL ofmethanol. This solution is cooled in an ice bath and sodiumcyanoborohydride (30.1 g) is added in small portions over a 2-minuteperiod. The resulting suspension is stirred mechanically and over thenext 30 minutes enough concentrated hydrochloric acid solution is addeddropwise to the reaction mixture to maintain a pH of about 4. Thesolvent is removed in vacuo to leave a semisolid residue which isdissolved in 300 mL of a 10% solution of hydrochloric acid in a wellventilated fume hood. This solution is diluted with an equal volume ofacetone and refluxed for 2 hours. The volatile components of the mixtureare removed in vacuo and the residue is cooled in an ice bath and madebasic with concentrated ammonium hydroxide. The white solid which formsis recrystallized from ethyl acetane-heptane to give 52.4 g of the titlecompound; mp 142-144° C.

EXAMPLE B

4-4-(2-Pyridinyl)-1-piperazinylcyclohexanone oxime.

A solution of 45.0 g of 4-[4-(2-pyridinyl)-1piperazinyl]cyclohexanone(Example A) in 350 mL absolute ethanol is treated with 13.55 g ofhydroxylamine hydrochloride and 19.7 g of triethylamine. The solution isrefluxed for 16 hours. After cooling the mixture to room temperature, awhite solid is filtered and washed several times with ethyl acetate.This solid is dried in vacuo and identified as the title compound; mp186-189° C. (37.8 g).

In a process analogous to Example B using appropriate starting materialsthe corresponding oximes (Examples C to G) are prepared as follows:

EXAMPLE C

4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexanone oxime; mp 185-186°C.

EXAMPLE D

4-[[4-(2-Pyridinyl)-1-piperazinyl]methyl]cyclo hexanone oxime.

EXAMPLE E

4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclo hexanone oxime; mp165-175° C.

EXAMPLE F

4-[2-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)ethyl]cyclohexanone oxime; mp165-173° C.

EXAMPLE G

4-[2-[3,6-Dihydro-4-(2-pyridinyl)-1(2H)-pyridinyl]ethyl]cyclohexanoneoxime; mp 172-179° C.

we claim:
 1. A compound of Formula I ##STR66## wherein R is --OR³,wherein R³ is hydrogen, lower alkyl, cycloalkyl of from three- toseven-member saturated hydrocarbon ring, cycloalkylalkyl wherein thecycloalkyl group is as defined above and the attached alkyl group isfrom one- to six-carbon atoms, phenyl lower alkyl, phenyl lower alkylsubstituted by one to four substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower thioalkoxy, halogen andtrifluoromethyl, lower alkanoyl, phenylcarbonyl, phenylcarbonylsubstituted by one to four substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower thioalkoxy, halogen andtrifluoromethyl, or phenyl lower alkanoyl, phenyl lower alkanoylsubstituted by one to four substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower thioalkoxy andtrifluoromethyl, ##STR67## wherein R⁴ and R⁵ are each independentlyhydrogen, lower alkyl, cycloalkyl of from three- to seven-membersaturated hydrocarbon ring, cycloalkylalkyl wherein the cycloalkyl groupis as defined above and the attached alkyl group is from one- tosix-carbon atoms, phenyl, phenyl substituted by one to four substituentsselected from the group consisting of lower alkyl, lower alkoxy, lowerthioalkoxy, halogen and trifluoromethyl, 2-, 3-, or 4-pyridinyl, 2-, 3-,or 4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-,4-, or 5-pyrimidinyl, 2-, 4-, or 5-pyrimidinyl substituted by loweralkyl, lower alkoxy, or halogen, 2-pyrazinyl, 2-pyrazinyl substituted bylower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl, 2- or 3-thienylsubstituted by lower alkyl or halogen, 2- or 3-furanyl, 2- or 3-furanylsubstituted by lower alkyl or halogen, 2-, 4-, or 5, thiazolyl, 2-, 4-,or 5-thiazolyl substituted by lower alkyl or halogen, phenyl loweralkyl, phenyl lower alkyl substituted by one to four substituentsselected from the group consisting of lower alkyl, lower alkoxy, lowerthioalkoxy, halogen and trifluoromethyl, 2-, 3-, or 4-pyridinyl loweralkyl, 2-3-, or 4-pyridinyl lower alkyl substituted by lower alkyl,lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl lower alkyl, 2-, 4-,or 5-pyrimidinyl lower alkyl substituted by lower alkyl, lower alkoxy,or halogen, 2-pyrazinyl lower alkyl, 2-pyrazinyl lower alkyl substitutedby lower alkyl, lower alkoxy or halogen, 2- or 3-thienyl lower alkyl, 2-or 3-thienyl lower alkyl substituted by lower alkyl or halogen, 2- or3-furanyl lower alkyl, 2- or 3-furanyl lower alkyl substituted by loweralkyl or halogen, 2-, 4-, or 5-thiazolyl lower alkyl, 2-, 4-, or5-thiazolyl lower alkyl substituted by lower alkyl or halogen, loweralkyanoyl, cycloalkanoyl, cycloalkylalkanoyl, phenyl lower alkanoyl,phenyl lower alkanoyl substituted by one to four substituents selectedfrom the group consisting of lower alkyl, lower alkoxy, lower thioalkoxyand trifluoromethyl, 2-, 3-, or 4-pyridinyl lower alkanoyl, 2-, 3-, or4-pyridinyl lower alkanoyl substituted by lower alkyl, lower alkoxy, orhalogen, 2-, 4-, or 5-pyrimidinyl lower alkanoyl, 2-, 4-, or5-pyrimidinyl lower alkanoyl substituted by lower alkyl, lower alkoxy,or halogen, 2-pyrazinyl lower alkanoyl, 2-pyrazinyl lower alkanoylsubstituted by lower alkyl, lower alkoxy or halogen, 2- or 3-thienyllower alkanoyl, 2- or 3-thienyl lower alkanoyl substituted by loweralkyl or halogen, 2- or 3-furanyl lower alkanoyl, 2- or 3-furanyl loweralkanoyl substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyllower alkanoyl, 2-, 4-, or 5-thiazolyl lower alkanoyl substituted bylower alkyl or halogen, phenylcarbonyl, phenylcarbonyl substituted byone to four substituents selected from the group consisting of loweralkyl, lower alkoxy, lower thioalkoxy, halogen and trifluoromethyl, 2-,3-, or 4-pyridinylcarbonyl substituted by lower alkyl, lower alkoxy, orhalogen, 2-, 4-, or 5-pyrimidinylcarbonyl, 2-, 4-, or5-pyrimidinylcarbonyl substituted by lower alkyl, lower alkoxy, orhalogen, 2-pyrazinylcarbonyl, 2-pyrazinylcarbonyl substituted by loweralkyl, lower alkoxy, or halogen, 2- or 3-thienylcarbonyl, 2- or3-thienylcarbonyl substituted by lower alkyl or halogen, 2- or3-furanylcarbonyl, 2- or 3-furanylcarbonyl substituted by lower alkyl orhalogen, 2-, 4-, or 5-thiazolylcarbonyl, 2-, 4-, or 5-thiazolylcarbonylsubstituted by lower alkyl or halogen, or R⁴ and R⁵ are taken togetherwith the nitrogen atom to which they are attached to form a ring denotedby ##STR68## wherein p is zero or an integer from 1 to 4 and R⁶ ishydrogen, lower alkyl, cycloalkyl of from three- to seven-membersaturated hydrocarbon ring, cycloalkylalkyl wherein the cycloalkyl groupis as defined above and the attached alkyl group is from one- tosix-carbon atoms, ##STR69## wherein X is oxygen or sulfur or ##STR70##wherein R⁶ is as defined above, or ##STR71## wherein R⁴ and R⁵ are eachindependently hydrogen, lower alkyl, cycloalkyl of from three- toseven-member saturated hydrocarbon ring, cycloalkylalkyl wherein thecycloalkyl group is as defined above and the attached alkyl group isfrom one- to six-carbon atoms, phenyl, phenyl substituted by one to foursubstituents selected from the group consisting of lower alkyl, loweralkoxy, lower thioalkoxy, halogen and trifluoromethyl, phenyl loweralkyl, phenyl lower alkyl substituted by one to four substituentsselected from the group consisting of lower alkyl, lower alkoxy, lowerthioalkoxy, halogen and trifluoromethyl, lower alkanoyl, phenyl loweralkanoyl, phenyl lower alkanoyl substituted by one to four substituentsselected from the group consisting of lower alkyl, lower alkoxy, lowerthioalkoxy and trifluoromethyl, phenylcarbonyl, phenylcarbonylsubstituted by one to four substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower thioalkoxy, halogen andtrifluoromethyl, or R⁴ and R⁵ are taken together with the oxygen andnitrogen atoms to which they are attached to form a ring denoted by##STR72## wherein q is an integer from 2 to 3 and R⁶ is as definedabove; m is zero or an integer from 1 to 2;R¹ is hydrogen; or when R is--OR³ wherein R³ is cycloalkyl of from three- to seven-member saturatedhydrocarbon ring or cycloalkylalkyl wherein the cycloalkyl group is asdefined above and the attached alkyl group is from one- to six-carbonatoms, ##STR73## wherein R⁴ and R⁵ are each independently cycloalkyl offrom three- to seven-member saturated hydrocarbon ring, cycloalkylalkylwherein the cycloalkyl group is as defined above and the attached alkylgroup is from one- to six-carbon atoms, 2-, 3-, or 4-pyridinyl, 2-, 3-,or 4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-,4-, or 5-pyrimidinyl, 2-, 4-, or 5-pyrimidinyl substituted by loweralkyl, lower alkoxy, or halogen, 2-pyrazinyl, 2-pyrazinyl substituted bylower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl, 2- or 3-thienylsubstituted by lower alkyl or halogen, 2- or 3- furanyl, 2- or 3-furanylsubstituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl, 2-, 4-,or 5-thiazolyl substituted by lower alkyl or halogen, 2-, 3-, or4-pyridinyl lower alkyl, 2-, 3-, or 4-pyridinyl lower alkyl substitutedby lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl loweralkyl, 2-, 4-, or 5-pyrimidinyl lower alkyl substituted by lower alkyl,lower alkoxy, or halogen, 2-pyrazinyl lower alkyl, 2-pyrazinyl loweralkyl substituted by lower alkyl, lower alkoxy, or halogen, 2- or3-thienyl lower alkyl, 2- or 3-thienyl lower alkyl substituted by loweralkyl or halogen, 2- or 3-furanyl lower alkyl, 2- or 3-furanyl loweralkyl substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyllower alkyl, 2-, 4-, or 5-thiazolyl lower alkyl substituted by loweralkyl or halogen, cycloalkanoyl, cycloalkylalkanoyl, 2-, 3-, or4-pyridinyl lower alkanoyl, 2-, 3-, or 4-pyridinyl lower alkanoylsubstituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or5-pyrimidinyl lower alkanoyl, 2-, 4-, or 5-pyrimidinyl lower alkanoylsubstituted by lower alkyl, lower alkoxy, or halogen, 2-pyrazinyl loweralkanoyl, 2-pyrazinyl lower alkanoyl substituted by lower alkyl, loweralkoxy or halogen, 2- or 3-thienyl lower alkanoyl, 2- or 3-thienyl loweralkanoyl substituted by lower alkyl or halogen, 2- or 3-furanyl loweralkanoyl, 2- or 3-furanyl lower alkanoyl substituted by lower alkyl orhalogen, 2-, 4-, or 5-thiazolyl lower alkanoyl, 2-, 4-, or 5-thiazolyllower alkanoyl substituted by lower alkyl or halogen, 2-, 3-, or4-pyridinylcarbonyl, 2-, 3-, or 4-pyridinylcarbonyl substituted by loweralkyl, lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinylcarbonyl, 2-,4-, or 5-pyrimidinylcarbonyl substituted by lower alkyl, lower alkoxy,or halogen, 2-pyrazinylcarbonyl, 2-pyrazinylcarbonyl substituted bylower alkyl, lower alkoxy, or halogen, 2- or 3-thienylcarbonyl, 2- or3-thienylcarbonyl substituted by lower alkyl or halogen, 2- or3-furanylcarbonyl, 2- or 3-furanylcarbonyl substituted by lower alkyl orhalogen, 2-, 4-, or 5-thiazolylcarbonyl, 2-, 4-, or 5-thiazolylcarbonylsubstituted by lower alkyl or halogen, or R⁴ and R⁵ are taken togetherwith the nitrogen atom to which they are attached to form a ring denotedby ##STR74## wherein p is zero or an integer from 1 to 4 and R⁶ iscycloalkyl of from three- to seven-member saturated hydrocarbon ring,cycloalkylalkyl wherein the cycloalkyl group is as defined above and theattached alkyl group is from one- to six-carbon atoms, or ##STR75##wherein R⁶ is as defined above, or ##STR76## wherein R⁴ and R⁵ are eachindependently cycloalkyl of from three- to seven-member saturatedhydrocarbon ring or cycloalkylalkyl wherein the cycloalkyl group is asdefined above and the attached alkyl group is from one- to six-carbonatoms, or R⁴ and R⁵ are taken together with the oxygen and nitrogenatoms to which they are attached to form a ring denoted by ##STR77##wherein q is an integer from 2 to 3 and R⁶ is cycloalkyl of from three-to seven-member saturated hydrocarbon ring, or cycloalkylalkyl whereinthe cycloalkyl group is as defined above and the attached alkyl group isfrom one- to six-carbon atoms R¹ is additionally phenyl, phenylsubstituted by one to four substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower thioalkoxy, halogen andtrifluoromethyl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinylsubstituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 5-,pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl,lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted bylower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2-or 3-furanyl substituted by lower alkyl or halogen, 2-, 4, or5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl orhalogen; n is zero or an integer from 1 to 4; R² is ##STR78## wherein R⁷is phenyl, phenyl substituted by one to four substituents selected fromthe group consisting of lower alkyl, lower alkoxy, lower thioalkoxy,halogen and trifluoromethyl. 2-, 3-, or 4-pyridinyl or 2-, 3-, or4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-,4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by loweralkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2-, or 3-thienyl or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2-or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl orhalogen; and the corresponding cis and trans isomers thereof; or apharmaceutically acceptable acid addition salt thereof.
 2. A compoundaccording to claim 1, in which R is --OR³, wherein R³ is hydrogen orlower alkanoyl ##STR79## wherein R⁴ is hydrogen, cycloalkyl of fromthree- to seven-member saturated hydrocarbon ring, cycloalkylalkylwherein the cycloalkyl group is as defined above and the attached alkylgroup is from one- to six-carbon atoms, lower alkanoyl, phenylcarbonyl,phenylcarbonyl substituted by one to four substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower thioalkoxy, halogenand trifluoromethyl, phenyl lower alkanoyl, phenyl lower alkanoylsubstituted by one to four substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower thioalkoxy andtrifluoromethyl, or 2-, 3-, or 4-pyridinylcarbonyl, 2-, 3-, or4-pyridinylcarbonyl substituted by lower alkyl, lower alkoxy, orhalogen, 2-, 4-, or 5-pyrimidinylcarbonyl, 2-, 4-, or5-pyrimidinylcarbonyl substituted by lower alkyl, lower alkoxy, orhalogen, 2-pyrazinylcarbonyl, 2-pyrazinylcarbonyl substituted by loweralkyl, lower alkoxy, or halogen, b 2- or 3-thienylcarbonyl, 2- or3-thienylcarbonyl substituted by lower alkyl or halogen, 2- or3-furanylcarbonyl, 2- or 3-furanylcarbonyl substituted by lower alkyl orhalogen, 2-, 4-, or 5-thiazolylcarbonyl, 2-, 4-, or 5-thiazolylcarbonylsubstituted by lower alkyl or halogen and R⁵ is hydrogen or lower alkylor; ##STR80## wherein one of R⁴ or R⁵ is hydrogen and the other ishydrogen, lower alkyl, cycloalkyl of from three- to seven-membersaturated hydrocarbon ring, cycloalkylalkyl wherein the cycloalkyl groupis as defined above and the attached alkyl group is from one- tosix-carbon atoms, phenyl, phenyl substituted by one to four substituentsselected from the group consisting of lower alkyl, lower alkoxy, lowerthioalkoxy, halogen and trifluoromethyl, or lower alkanoyl;m is zero; R¹is hydrogen; n is zero or an integer from 1 to 3; and R² is ##STR81##wherein R⁷ is phenyl, phenyl substituted by para lower alkyl, para loweralkoxy, para lower thioalkoxy, or para halogen, 2-, 3-, or 4-pyridinyl,2- or 3-furanyl, 2- or 3-thienyl, 2-, 4-, or 5-thiazolyl, or 2-, 4-, or5-pyrimidinyl.
 3. A compound according to claim 2, in which R is --OH,##STR82## wherein R⁴ is hydrogen, cycloalkyl of from three- toseven-member saturated hydrocarbon ring, cycloalkylalkyl wherein thecycloalkyl group is as defined above and the attached alkyl group isfrom one- to six-carbon atoms, lower alkanoyl, phenylcarbonyl,phenylcarbonyl substituted by one to four substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower thioalkoxy, halogenand trifluoromethyl or 2-, 3-, or 4-pyridinylcarbonyl, 2-, 3-, or4-pyridinylcarbonyl substituted by lower alkyl, lower alkoxy, orhalogen, 2-, 4-, or 5-pyrimidinylcarbonyl, 2-, 4-, or5-pyrimidinylcarbonyl substituted by lower alkyl, lower alkoxy, orhalogen, 2-pyrazinylcarbonyl, 2-pyrazinylcarbonyl substituted by loweralkyl, lower alkoxy, or halogen, 2- or 3-thienylcarbonyl, 2- or3-thienylcarbonyl substituted by lower alkyl or halogen, 2- or3-furanylcarbonyl, 2- or 3-furanylcarbonyl substituted by lower alkyl orhalogen, 2-, 4-, or 5-thiazolylcarbonyl, 2-, 4-, or 5-thiazolylcarbonylsubstituted by lower alkyl or halogen and R⁵ is hydrogen or lower alkyl;or ##STR83## wherein R⁴ is hydrogen, lower alkyl, cycloalkyl of fromthree- to seven-member saturated hydrocarbon ring, cycloalkylalkylwherein the cycloalkyl group is as defined above and the attached alkylgroup is from one- to six-carbon atoms, phenyl, phenyl substituted byone to four substituents selected from the group consisting of loweralkyl, lower alkoxy, lower thioalkoxy, halogen and trifluoromethyl, orlower alkanoyl;m is zero; R¹ is hydrogen; n is zero or an integer from 1to 2; and R² is ##STR84## wherein R⁷ is hydrogen, phenyl, phenylsubstituted by para lower alkyl or para halogen, 2-, 3-, or 4-pyridinyl,2- or 3-thienyl, 2-, 4-, or 5-thiazolyl, or 2-, 4-, or 5-pyrimidinyl. 4.A compound according to claim 3 selected from the group consistingoftrans N-[4-[4-(2-Pyridinyl)-1-piperazinyl]cyclohexyl]benzamide; transN-[4-[4-(2-Pyridinyl)-1-piperazinyl]cyclohexyl]-2-methoxybenzamide;trans N-Methyl-N-[4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexyl]benzamide;trans 4-Chloro-N-[4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexyl]benzamide;transN-[4-[4-(2-Pyridinyl)-1-piperazinyl]cyclohexyl]-2-thiophenecarboxamide;transN-[4-[4-(2-Pyridinyl)-1-piperazinyl]cyclohexyl]-3-thiophenecarboxamide;trans N-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]benzamide;transN-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]-2-thiophenecarboxamide;transN-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]-3-thiophenecarboxamide;transN-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]-3-pyridinecarboxamide;transN-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]cyclohexanecarboxamide;trans 4-Methyl-N-[4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexyl]benzamide;trans N-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;cis N-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;trans4-Methyl-N-[4-[2-[4-(2pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;cis4-Methyl-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamidecis4-Chloro-N-[4-[2-[4-(2pyridinyl)-1piperazinyl]ethyl]cyclohexyl]benzamide;trans4-Chloro-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;trans N-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]acetamide;trans3,4-Dichloro-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;trans N-[4-]]4-(2-Pyridinyl)-1-piperazinyl]methyl]cyclohexyl]benzamide;cis3,4-Dichloro-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;trans-4-Chloro-N-[4-(3,6-dihydro-4-phenyl)-1(2H)-pyridinyl)cyclohexyl]benzamide;transN-[4-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)cyclohexyl]-4-fluorobenzamide;transN-[4-]]4-(2-Pyridinyl)-1-piperazinyl]methyl]cyclohexyl]-3-thiophenecarboxamide;trans4-Methoxy-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;cisN-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]-3-thiophenecarboxamide;cis N-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]-2-furancarboxamide; cis4-Methoxy-N-[4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]benzamide;cisN-[4-[2-[(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)ethyl]cyclohexyl]benzamide;cisN-[4-[2-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)ethyl]cyclohexyl]-2-thiophenecarboxamide;transN-[4-[2-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)ethyl]cyclohexyl]-2-thiophenecarboxamide;transN-[4-[2-(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)ethyl]cyclohexyl]benzamide;transN-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]-2-ethyl]cyclohexyl]-2-thiophenecarboxamide;and cisN-[4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]cyclohexyl]-2-thiophenecarboxamide.5. A method of treating schizophrenia comprising administering to a hostsuffering therefrom a therapeutic effective amount of a compoundaccording to claim 1 in unit dosage form.
 6. A method of treatingdepression comprising administering to a host suffering therefrom atherapeutic effective amount of a compound according to claim 1 in unitdosage form.
 7. A pharmaceutical composition adapted for administrationas a dopaminergic, antipsychotic, antihypertensive or antidepressantagent comprising a therapeutic effective amount of a compound accordingto claim 1 in admixture with a pharmaceutically acceptable excipient,diluent or carrier.